Certain isonicotinic aod-n-oxtoe poly-



v es Patent CERTAIN TSONICOTINIC A CID-N-OXIDE POLY w HALOGEN DIPHENYL ALKYL AMIDES Heinrich Leditschke, Frankfurt .am. Main, Heinrich Rolly, Kelkheim (Tauuus), and Heinz Schmidt-Ruppin, Bad Soden .(Taunus), Germany, assignors to Farbwerke 'Hoechst Aktieugesellscha'ft vorma'ls Meister Lucius &

Bruning, Frankfurt am Main, Germany, a corporation .of Germany g I it No Drawing. Filed Dec. 2, 195$,Ser. No. 777,575 Claims priority, application Germany Dec. 6, 1957 3 Claims. '(Cl. 260-295) The present invention relates to isonicotinic .acid-'N- oxide-amides of the general formula Hal in whichHal represents halogen, ,nrepresents the inte er 1 or 2, and x stands for hydrogen, halogen vor the methyl 2,945,040 Patented vJuly 12,196Q

and, on the other hand the compounds of the general formula Hal obtainable by reaction of isonicotinic acid with substituted alkyl-amines.

As reactive derivatives of the isonicotinic acid-N-oxide there may be mentioned, for example, the halides, esters, azides vand the hydrohalic-acid salts. The-corresponding acid chloride can favorably be used. a

As amines of the above-mentioned general formula. there are mentioned:

3 ,3 (p, p'-dichloro diphenyl) -propylamine,

V 3 p-fluorophenyl) -3- (p-chlorophenyl) -propylamine,

group which are distinguished by an excellent efficiency on influenza infections. The invention further provides a process for preparing 'these compounds by reacting isonicotinic acid-N-oxide-.or its .reactiveaderivatiyes with substituted :alkyhamines .of the formula OQQHM 1 inwliic'h'HaLln and xhave the meanings given above or by oxidizing 'isonicotinic acid amides of .the formula .Hal

ntN-tcnor-on H51 3-(o-chlorophenyl) -3-(p-chlorophenyl) -propylamine,

S-(m-chlororihenyl -3-(p-chlorophenyl) -propylaniine,

3-(rn-methyl-p-ch'lorophenyl) 3 '(p-ehlorop'henyl) propylamine,

3 -(2',4' -dichlorophen yl) -3-(-p-chlorophenyl -propylamine.

The above-mentioned isonicotinic acid amides can he prepared, for instance, by reaction of isonicotinieacids or their reactive derivatives, for example with t'helabovementioned amines, it being possible to react the free isonictonic acids with the amines .by short heating to an elevated temperature or by .using the reactive derivatives, for example the halides, esters, .azides or thehydrohalic acid salts 'of isonicotinic acids, starting the reaction at room temperature and terminating it at an elevated temperature. a V

According to one method of operation of the process the oxidation of the isonicotin'ic acid amide with organic per acids .is suitably carried out a temperature between about 60 C. and about 80 C." As organic per-acids there enter into consideration in addition to peracetic acid for instance perbenzoic acid or monop'erphthalic acid. When peracetic acid is used it is favorable to apply as solvent glacial acetic acid which simultaneously serves for the preparation of peracetic acid. When using, however, other per acids, for instance perbenzoic acid, it is of-advantage to carry out the reaction in an inert solvent which does not react with the starting substances hem zene being particularly appropriate for this purpose.

When using as starting substances instead of the .free isonicotinic acid-N-oxides their derivatives .it is advan tageous to vary the conditions of reaction accordingly.- In the latter case-it may be favorable to add an inert solvent, such as benzene, toluene, xylene, acetone for ether and to use organic bases, such aspyridine, quinoline ortrimethylamine. An excess of the amineused as reactant can, however, likewise be used as acid binding agent. The reaction is'favorablY eflfeeted at room temperature or at a n'roderately decreased temperature, :prefe erably between 5 C. and +20 0.; cooling with ice is -favorably applied. The "reaction can be terminated by subsequent heating on the steam bath.

The above-mentioned method of operation is favorably Hal in which Hal, n and x have the meanings given above obtained by the process of the invention are characterized by an extraordinarily good efficiency on influenza infections. For example, the isonicotinic acid-N-oxide [3,3-

h Il um-chloride and chlorobenzene into 245 parts of 5,5- -(p,p'-dichloro-diphenyl)propionic acid, melting at 190- 191 C. 267 parts of this compound are transformed with 1340 parts by volume of thionyl-chloride into the acid chloride (335 parts) and the latter compound is reacted with 2000 parts by volume of concentrated ammonia in order to obtain 184 parts of ,3,}8-(p,p'-dichlorodiphenyl) -propionic acid amide which melts at l53154 C. 222 parts of 5,5-(p,p-dichloro-diphenyl)-propionic acid amide are treated with 222 parts by volume of thionyl chloride and there are obtained 106 parts of 3,18- (p,p-dichloro-diphenyl)-propionitrile melting at 80-8-1 C. 100 parts of this compound are hydrogenated in order to obtain 85 parts'of 3,3(p,p'-dichloro-diphenyl)- propylamine boiling at 204-206 C. under a pressure of 3 Hg. A colorless oil is obtained.

EXAMPLE 2 ls onicotinic acid N oxide-[3,3-(p,p'-dichloro-diphenylpropyl)-(1)]-amide 39.4. parts, of isonicotinic acid-3,3-(p,p'-dichloro-diphenyl)-propyl-(1)-amide are heated with 46 parts of (p,p'-dichlorophenyl)-propyl-(1) l-arnide upon oral ad- A ministration of 4 times 0.625 mg./20 grams provokes an average delay of influenza APR8 of 27.3% in mice. When the substance is subcutaneously applied the delay of influenza APR8 amounts to an average of 42.5%

:with 4 doses of 2.5 ng/20 grams each. The products a of the invention likewise act on dogs distemper.

. The compounds can be worked up topharmaceutical preparations, if necessary in admixture with pharmaceutically usual carrier substances such as starch, lactose,

talcum tragacamh magnesmm'steamte' They there Isonicotinic acid -N oxide-[3-(3',4-dichlorophenyl)-3- fore, can be applied for instance in the form of tablets, dragees, capsules, drops, emulsions and ampoulesi The following examples serve to illustrate the invention but they are not intended to limit it thereto, the parts being by weight, unless otherwise stated.

EXAMPLE 1 isonicotinic acid-N-oxid e [3,3-(p,p-dichlofodiphenyl) propy l-(l J-dmide hydrogen peroxide of 30% strength and 100 parts by volume of glacial acetic acid in the oil bath at an external temperature of 90 C. at first for 3 hours and then for 8 hours to 110 C. The major part of the solvent is then i distilled ofl? under reduced pressure, 200 parts by volume of water are added to the residue and the water is again steamed oil? under reduced pressure. Two times 200 parts by volume of acetone are added to the residue and the acetone is eliminated each time by steaming. By dissolving the crystalline residue in 1000 parts by volume of acetone, filtering and concentrating the acetone by evaporation in order to obtain 100 parts by volume, there are obtained 28 parts of isonicotinic acid-N-oxile-[3,3-(p,p'- dichloro-diphenyl-propyl)-(1)l-amide in the form of colorless crystals melting at 128129 C. (with decomposition). The product crystallizes with half a mol of acetone.

EXAMPLE 3 42 parts of isonicotinic acid-3-(3',4-dichlorophenyl) -3- (4'-chloro-phenyl)propyl-(1)-amide are heated with 46 parts of hydrogen peroxide of 30% strength and 100 245 parts of isonicotinic acidN-oxide'chloride-hydrochloride are introduced, while cooling with ice within 10 minutes into 24 parts of 3,3-(p,p'-dichlorodiphenyl)- propylamine in such a manner that the temperature does not exceed 20 C. The reaction mixture is then heated The crude ing at 125126 C. After double recrystallization from acetone, at first with use of charcoal, crystals are obtained melting at 128129 C. (with decomposition) and which crystallize with half a mol of acetone.

' he 3,3-(p,p-dichlorophenyl)-propylamine is prepared in the following manner:

- 274 parts of para-chlorocinnamic acid 'are converted by v means of 600 parts of finely-pulverized anhydrous 1} parts by volume of glacial acetic acid in the oil bath at an external temperature of C. at first for Shours and then for 8 hours to C. The reaction mixture is then concentrated by evaporation under reduced pressure on the steam'bath, 250 parts by volume of water are added to the residue and the water is again removed by evaporation under reduced pressure. To the residue there are added three times 200 parts by volume each time of acetone and the acetone is eliminated by evaporation. The residue, recrystallized from a small amount of acetone yields 23.6 parts of isonicotinic acid-Noxide- [3-(3',4' -dichlorophenyl) -3-(4'-chlorophenyl) propyl- (1)1-amide which melts at 1l6-1l7 C. with decomposition.

We claim:

1. Isonicotinic acid-N-oxide-amides of the general formula Hal wherein Hal represents a halogen atom having a molecu- 3. The compound of the formula lar weight up to 35.5, n is an integer from 1 to 2, and x 01 is -a member of the group consisting of hydrogen, halogen and methyl.

2. The compound of the formula 5 Q Q (BO-NH-OHa-CHz-C I References Cited in the file of this patent UNITED STATES PATENTS 2,843,594 Leditschke et a1 July 15, 1958 

1. ISONICOTINIC ACID-N-OXIDE-AMIDES OF THE GENERAL FORMULA 